Targeted inhibition of mTORC1 and mTORC2 by active-site mTOR inhibitors has cytotoxic effects in T-cell acute lymphoblastic leukemia
Targeted inhibition of mTORC1 and mTORC2 by active-site mTOR inhibitors has cytotoxic effects in T-cell acute lymphoblastic leukemia
复制标题
DOI：
10.1038/leu.2011.20
复制
发表时间：
2011-05-01
期刊：
影响因子：
11.4
通讯作者：
Martelli, A. M.
中科院分区：
文献类型：
--
作者：
Evangelisti, C.;Ricci, F.;Martelli, A. M.
哺乳动物雷帕霉素(MTOR)丝氨酸/苏氨酸激酶的靶标属于两个多蛋白复合体，称为mTORC1和mTORC2。MTOR产生的信号通过控制促进增殖和存活的基因的mRNA翻译，在白血病细胞生物学中发挥关键作用。然而，雷帕霉素对mTORC1的变构抑制对T细胞急性淋巴细胞白血病(T-ALL)的影响不大。最近，针对mTOR激酶活性部位的ATP竞争性抑制剂已经被开发出来。在这项研究中，我们探索了活性部位mTOR抑制剂对T-ALL细胞系和显示mTORC1和mTORC2激活的T-ALL患者的原始样本的治疗潜力。这些抑制剂通过诱导细胞周期停滞于G(0)/G(1)期、细胞凋亡和自噬来影响T-ALL细胞的活性。Western印迹分析显示Ser 473Akt去磷酸化(表明mTORC2被抑制)和mTORC1下游靶向去磷酸化。与雷帕霉素不同，我们发现活性部位mTOR抑制剂处理的T-ALL细胞株的mRNA翻译受到显著抑制。这些抑制剂与长春新碱和Bcl2抑制剂ABT-263有很强的协同作用。值得注意的是，这些药物针对的是患者样本中可能的白血病启动细胞亚群(CD34(+)/CD7(-)/CD4(-))。总之，这些抑制剂显示了显著的抗白血病活性，这强调了它们作为治疗T-ALL的临床候选药物的未来发展。白血病(2011年)25781-791；doi：10.1038/leu 2011.20；2011年2月18日在线发布
The mammalian Target Of Rapamycin (mTOR) serine/threonine kinase belongs to two multi-protein complexes, referred to as mTORC1 and mTORC2. mTOR-generated signals have critical roles in leukemic cell biology by controlling mRNA translation of genes that promote proliferation and survival. However, allosteric inhibition of mTORC1 by rapamycin has only modest effects in T-cell acute lymphoblastic leukemia (T-ALL). Recently, ATP-competitive inhibitors specific for the mTOR kinase active site have been developed. In this study, we have explored the therapeutic potential of active-site mTOR inhibitors against both T-ALL cell lines and primary samples from T-ALL patients displaying activation of mTORC1 and mTORC2. The inhibitors affected T-ALL cell viability by inducing cell-cycle arrest in G(0)/G(1) phase, apoptosis and autophagy. Western blot analysis demonstrated a Ser 473 Akt dephosphorylation (indicative of mTORC2 inhibition) and a dephosphorylation of mTORC1 downstream targets. Unlike rapamycin, we found a marked inhibition of mRNA translation in T-ALL cell lines treated with active-site mTOR inhibitors. The inhibitors strongly synergized with both vincristine and the Bcl-2 inhibitor, ABT-263. Remarkably, the drugs targeted a putative leukemia-initiating cell sub-population (CD34(+)/CD7(-)/CD4(-)) in patient samples. In conclusion, the inhibitors displayed remarkable anti-leukemic activity, which emphasizes their future development as clinical candidates for therapy in T-ALL. Leukemia (2011) 25, 781-791; doi: 10.1038/leu.2011.20; published online 18 February 2011